Biochemical Genetics Group: The Laboratory continues to search for quantitative and/or qualitative disease-associated changes in gene expression and protein function. In this effort, we have identified an 18,000 dalton protein in cerebrospinal fluid which is increased two fold or more in individuals with both Alzheimer's disease (AD) and schizophrenia. This protein has been tentatively identified as a variant of the alpha chain of haptoglobin. In addition, the Laboratory has established two models for understanding the altered protein content that is exhibited by AD-afflicted tissues. Using a well characterized animal model for AD, we have demonstrated an induction of amyloid precursor protein (APP) In the cerebral cortex of rats with lesions of the nucleus basalis of Meynert. This treated cortex represents an in situ model for elucidating the normal function of APP in brain. We have also developed a cell culture model of the Alzheimer's disease brain using neuronal PC 12 cells that have been treated by heat shock to understand the role of heat shock 70 proteins in the abnormal modifications of APP and tau. After this stress, tau is abnormally phosphorylated to form A68, the primary protein constituent of neurofibrillary tangles. We have also been studying protein alterations associated with mutations affecting neurally regulated circadian pacemakers, as well as conducting studies to identify proteins that are essential for normal circadian function. These investigations will allow us to understand the pathological consequences of these proteins in degeneration of neurons in diseases and normal aging.